Journal Article > ResearchFull Text
Clin Infect Dis. 25 January 2024; Volume 78 (Issue 1); 164-171.; DOI:10.1093/cid/ciad589
Sauer SM, Mitnick CD, Khan UT, Hewison CCH, Bastard M, et al.
Clin Infect Dis. 25 January 2024; Volume 78 (Issue 1); 164-171.; DOI:10.1093/cid/ciad589
BACKGROUND
Quantification of recurrence risk following successful treatment is crucial to evaluating regimens for multidrug- or rifampicin-resistant (MDR/RR) tuberculosis (TB). However, such analyses are complicated when some patients die or become lost during post-treatment-follow-up.
METHODS
We analyzed data on 1,991 patients who successfully completed a longer MDR/RR-TB regimen containing bedaquiline and/or delamanid between 2015 and 2018 in 16 countries. Using five approaches for handling post-treatment deaths, we estimated the six-month post-treatment TB recurrence risk overall, and by HIV status. We used inverse-probability-weighting to account for patients with missing follow-up and investigated the impact of potential bias from excluding these patients without applying inverse-probability weights.
RESULTS
The estimated TB recurrence risk was 7.4 per 1000 (95% confidence interval (CI): 3.5,12.9) when deaths were handled as non-recurrences, and 7.6 per 1000 (95% CI: 3.6,13.1) when deaths were censored and inverse-probability weights were applied to account for the excluded deaths. The estimated risk of composite recurrence outcomes were 25.5 (95% CI: 15.4,38.1), 11.7 (95% CI: 6.5,18.3), and 8.6 (95% CI: 4.2,14.6) per 1000 for recurrence or 1) any death, 2) death with unknown or TB-related cause, 3) TB-related death, respectively. Corresponding relative risks for HIV status varied in direction and magnitude. Exclusion of patients with missing follow-up without inverse-probability-weighting had a small impact on estimates.
CONCLUSIONS
The estimated six-month TB recurrence risk was low, and the association with HIV status was inconclusive due to few recurrence events. Estimation of post-treatment recurrence will be enhanced by explicit assumptions about deaths and appropriate adjustment for missing follow-up data.
Quantification of recurrence risk following successful treatment is crucial to evaluating regimens for multidrug- or rifampicin-resistant (MDR/RR) tuberculosis (TB). However, such analyses are complicated when some patients die or become lost during post-treatment-follow-up.
METHODS
We analyzed data on 1,991 patients who successfully completed a longer MDR/RR-TB regimen containing bedaquiline and/or delamanid between 2015 and 2018 in 16 countries. Using five approaches for handling post-treatment deaths, we estimated the six-month post-treatment TB recurrence risk overall, and by HIV status. We used inverse-probability-weighting to account for patients with missing follow-up and investigated the impact of potential bias from excluding these patients without applying inverse-probability weights.
RESULTS
The estimated TB recurrence risk was 7.4 per 1000 (95% confidence interval (CI): 3.5,12.9) when deaths were handled as non-recurrences, and 7.6 per 1000 (95% CI: 3.6,13.1) when deaths were censored and inverse-probability weights were applied to account for the excluded deaths. The estimated risk of composite recurrence outcomes were 25.5 (95% CI: 15.4,38.1), 11.7 (95% CI: 6.5,18.3), and 8.6 (95% CI: 4.2,14.6) per 1000 for recurrence or 1) any death, 2) death with unknown or TB-related cause, 3) TB-related death, respectively. Corresponding relative risks for HIV status varied in direction and magnitude. Exclusion of patients with missing follow-up without inverse-probability-weighting had a small impact on estimates.
CONCLUSIONS
The estimated six-month TB recurrence risk was low, and the association with HIV status was inconclusive due to few recurrence events. Estimation of post-treatment recurrence will be enhanced by explicit assumptions about deaths and appropriate adjustment for missing follow-up data.
Journal Article > Short ReportFull Text
Clin Infect Dis. 25 January 2024; Volume 78 (Issue 1); 144-148.; DOI:10.1093/cid/ciad445
Lotia Farrukh I, Lachenal N, Adenov MM, Ahmed SM, Algozhin Y, et al.
Clin Infect Dis. 25 January 2024; Volume 78 (Issue 1); 144-148.; DOI:10.1093/cid/ciad445
Among 43 pregnant women receiving multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment with bedaquiline and/or delamanid, 98% had favorable treatment outcomes. Of 31 continued pregnancies, 81% had live births with no reported malformations, and 68% of neonates had normal birth weights. Effective MDR/RR-TB treatment during pregnancy can improve maternal outcomes without harming neonates.
Journal Article > Research
PLOS Glob Public Health. 28 April 2023; Volume 3 (Issue 4); e0000818.; DOI:10.1371/journal.pgph.0000818
Rodriguez CA, Lodi S, Horsburgh CR, Mitnick CD, Bastard M, et al.
PLOS Glob Public Health. 28 April 2023; Volume 3 (Issue 4); e0000818.; DOI:10.1371/journal.pgph.0000818
Clarity about the role of delamanid in longer regimens for multidrug-resistant TB is needed after discordant Phase IIb and Phase III randomized controlled trial results. The Phase IIb trial found that the addition of delamanid to a background regimen hastened culture conversion; the results of the Phase III trial were equivocal. We evaluated the effect of adding delamanid for 24 weeks to three-drug MDR/RR-TB regimens on two- and six-month culture conversion in the endTB observational study. We used pooled logistic regression to estimate the observational analogue of the intention-to-treat effect (aITT) adjusting for baseline confounders and to estimate the observational analogue of the per-protocol effect (aPP) using inverse probability of censoring weighting to control for time-varying confounding. At treatment initiation, 362 patients received three likely effective drugs (delamanid-free) or three likely effective drugs plus delamanid (delamanid-containing). Over 80% of patients received two to three Group A drugs (bedaquiline, linezolid, moxifloxacin/levofloxacin) in their regimen. We found no evidence the addition of delamanid to a three-drug regimen increased two-month (aITT relative risk: 0.90 (95% CI: 0.73–1.11), aPP relative risk: 0.89 (95% CI: 0.66–1.21)) or six-month culture conversion (aITT relative risk: 0.94 (95% CI: 0.84, 1.02), aPP relative risk: 0.93 (95% CI: 0.83, 1.04)). In regimens containing combinations of three likely effective, highly active anti-TB drugs the addition of delamanid had no discernible effect on culture conversion at two or six months. As the standard of care for MDR/RR-TB treatment becomes more potent, it may become increasingly difficult to detect the benefit of adding a single agent to standard of care MDR/RR-TB regimens. Novel approaches like those implemented may help account for background regimens and establish effectiveness of new chemical entities.
Journal Article > ResearchFull Text
Lancet Child Adolesc Health. 13 March 2023; Online ahead of print; DOI:10.1016/S2352-4642(23)00004-4
Gunasekera KS, Marcy O, Muñoz J, Lopez-Varela E, Sekadde MP, et al.
Lancet Child Adolesc Health. 13 March 2023; Online ahead of print; DOI:10.1016/S2352-4642(23)00004-4
BACKGROUND
Many children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies so far have been small and localised, with limited generalisability. We aimed to evaluate the performance of currently used diagnostic algorithms and to use prediction modelling to develop evidence-based algorithms to assist in tuberculosis treatment decision making for children presenting to primary health-care centres.
METHODS
For this meta-analysis, we identified individual participant data from a WHO public call for data on the management of tuberculosis in children and adolescents and referral from childhood tuberculosis experts. We included studies that prospectively recruited consecutive participants younger than 10 years attending health-care centres in countries with a high tuberculosis incidence for clinical evaluation of pulmonary tuberculosis. We collated individual participant data including clinical, bacteriological, and radiological information and a standardised reference classification of pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing treatment-decision algorithms. We then used the data to develop two multivariable prediction models that included features used in clinical evaluation of pulmonary tuberculosis-one with chest x-ray features and one without-and we investigated each model's generalisability using internal-external cross-validation. The parameter coefficient estimates of the two models were scaled into two scoring systems to classify tuberculosis with a prespecified sensitivity target. The two scoring systems were used to develop two pragmatic, treatment-decision algorithms for use in primary health-care settings.
FINDINGS
Of 4718 children from 13 studies from 12 countries, 1811 (38·4%) were classified as having pulmonary tuberculosis: 541 (29·9%) bacteriologically confirmed and 1270 (70·1%) unconfirmed. Existing treatment-decision algorithms had highly variable diagnostic performance. The scoring system derived from the prediction model that included clinical features and features from chest x-ray had a combined sensitivity of 0·86 [95% CI 0·68-0·94] and specificity of 0·37 [0·15-0·66] against a composite reference standard. The scoring system derived from the model that included only clinical features had a combined sensitivity of 0·84 [95% CI 0·66-0·93] and specificity of 0·30 [0·13-0·56] against a composite reference standard. The scoring system from each model was placed after triage steps, including assessment of illness acuity and risk of poor tuberculosis-related outcomes, to develop treatment-decision algorithms.
INTERPRETATION
We adopted an evidence-based approach to develop pragmatic algorithms to guide tuberculosis treatment decisions in children, irrespective of the resources locally available. This approach will empower health workers in primary health-care settings with high tuberculosis incidence and limited resources to initiate tuberculosis treatment in children to improve access to care and reduce tuberculosis-related mortality. These algorithms have been included in the operational handbook accompanying the latest WHO guidelines on the management of tuberculosis in children and adolescents. Future prospective evaluation of algorithms, including those developed in this work, is necessary to investigate clinical performance.
Many children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies so far have been small and localised, with limited generalisability. We aimed to evaluate the performance of currently used diagnostic algorithms and to use prediction modelling to develop evidence-based algorithms to assist in tuberculosis treatment decision making for children presenting to primary health-care centres.
METHODS
For this meta-analysis, we identified individual participant data from a WHO public call for data on the management of tuberculosis in children and adolescents and referral from childhood tuberculosis experts. We included studies that prospectively recruited consecutive participants younger than 10 years attending health-care centres in countries with a high tuberculosis incidence for clinical evaluation of pulmonary tuberculosis. We collated individual participant data including clinical, bacteriological, and radiological information and a standardised reference classification of pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing treatment-decision algorithms. We then used the data to develop two multivariable prediction models that included features used in clinical evaluation of pulmonary tuberculosis-one with chest x-ray features and one without-and we investigated each model's generalisability using internal-external cross-validation. The parameter coefficient estimates of the two models were scaled into two scoring systems to classify tuberculosis with a prespecified sensitivity target. The two scoring systems were used to develop two pragmatic, treatment-decision algorithms for use in primary health-care settings.
FINDINGS
Of 4718 children from 13 studies from 12 countries, 1811 (38·4%) were classified as having pulmonary tuberculosis: 541 (29·9%) bacteriologically confirmed and 1270 (70·1%) unconfirmed. Existing treatment-decision algorithms had highly variable diagnostic performance. The scoring system derived from the prediction model that included clinical features and features from chest x-ray had a combined sensitivity of 0·86 [95% CI 0·68-0·94] and specificity of 0·37 [0·15-0·66] against a composite reference standard. The scoring system derived from the model that included only clinical features had a combined sensitivity of 0·84 [95% CI 0·66-0·93] and specificity of 0·30 [0·13-0·56] against a composite reference standard. The scoring system from each model was placed after triage steps, including assessment of illness acuity and risk of poor tuberculosis-related outcomes, to develop treatment-decision algorithms.
INTERPRETATION
We adopted an evidence-based approach to develop pragmatic algorithms to guide tuberculosis treatment decisions in children, irrespective of the resources locally available. This approach will empower health workers in primary health-care settings with high tuberculosis incidence and limited resources to initiate tuberculosis treatment in children to improve access to care and reduce tuberculosis-related mortality. These algorithms have been included in the operational handbook accompanying the latest WHO guidelines on the management of tuberculosis in children and adolescents. Future prospective evaluation of algorithms, including those developed in this work, is necessary to investigate clinical performance.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 1 January 2023; Volume 27 (Issue 1); 34-40.; DOI:10.5588/ijtld.22.0324
Zeng C, Mitnick CD, Hewison CCH, Bastard M, Khan PY, et al.
Int J Tuberc Lung Dis. 1 January 2023; Volume 27 (Issue 1); 34-40.; DOI:10.5588/ijtld.22.0324
BACKGROUND
The WHO provides standardized outcome definitions for rifampicin-resistant (RR) and multidrug-resistant (MDR) TB. However, operationalizing these definitions can be challenging in some clinical settings, and incorrect classification may generate bias in reporting and research. Outcomes calculated by algorithms can increase standardization and be adapted to suit the research question. We evaluated concordance between clinician-assigned treatment outcomes and outcomes calculated based on one of two standardized algorithms, one which identified failure at its earliest possible recurrence (i.e., failure-dominant algorithm), and one which calculated the outcome based on culture results at the end of treatment, regardless of early occurrence of failure (i.e., success-dominant algorithm).
METHODS
Among 2,525 patients enrolled in the multi-country endTB observational study, we calculated the frequencies of concordance using cross-tabulations of clinician-assigned and algorithm-assigned outcomes. We summarized the common discrepancies.
RESULTS
Treatment success calculated by algorithms had high concordance with treatment success assigned by clinicians (95.8 and 97.7% for failure-dominant and success-dominant algorithms, respectively). The frequency and pattern of the most common discrepancies varied by country.
CONCLUSION
High concordance was found between clinician-assigned and algorithm-assigned outcomes. Heterogeneity in discrepancies across settings suggests that using algorithms to calculate outcomes may minimize bias.
The WHO provides standardized outcome definitions for rifampicin-resistant (RR) and multidrug-resistant (MDR) TB. However, operationalizing these definitions can be challenging in some clinical settings, and incorrect classification may generate bias in reporting and research. Outcomes calculated by algorithms can increase standardization and be adapted to suit the research question. We evaluated concordance between clinician-assigned treatment outcomes and outcomes calculated based on one of two standardized algorithms, one which identified failure at its earliest possible recurrence (i.e., failure-dominant algorithm), and one which calculated the outcome based on culture results at the end of treatment, regardless of early occurrence of failure (i.e., success-dominant algorithm).
METHODS
Among 2,525 patients enrolled in the multi-country endTB observational study, we calculated the frequencies of concordance using cross-tabulations of clinician-assigned and algorithm-assigned outcomes. We summarized the common discrepancies.
RESULTS
Treatment success calculated by algorithms had high concordance with treatment success assigned by clinicians (95.8 and 97.7% for failure-dominant and success-dominant algorithms, respectively). The frequency and pattern of the most common discrepancies varied by country.
CONCLUSION
High concordance was found between clinician-assigned and algorithm-assigned outcomes. Heterogeneity in discrepancies across settings suggests that using algorithms to calculate outcomes may minimize bias.
Journal Article > ResearchFull Text
Clin Infect Dis. 15 October 2022; Volume 75 (Issue 8); 1307-1314.; DOI:10.1093/cid/ciac176
Huerga H, Khan UT, Bastard M, Mitnick CD, Lachenal N, et al.
Clin Infect Dis. 15 October 2022; Volume 75 (Issue 8); 1307-1314.; DOI:10.1093/cid/ciac176
BACKGROUND
Concomitant use of bedaquiline (Bdq) and delamanid (Dlm) for multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) has raised concerns about a potentially poor risk-benefit ratio. Yet, this combination is an important alternative for patients infected with strains of TB with complex drug resistance profiles or who cannot tolerate other therapies. We assessed safety and treatment outcomes of MDR/RR-TB patients receiving concomitant Bdq and Dlm, along with other second-line anti-TB drugs.
METHODS
We conducted a multi-centric, prospective observational cohort study across 14 countries among patients receiving concomitant Bdq-Dlm treatment. Patients were recruited between April 2015 and September 2018 and were followed until the end of treatment. All serious adverse events and adverse events of special interest (AESI), leading to a treatment change, or judged significant by a clinician, were systematically monitored and documented.
RESULTS
Overall, 472 patients received Bdq and Dlm concomitantly. A large majority also received linezolid (89.6%) and clofazimine (84.5%). Nearly all (90.3%) had extensive disease; most (74.2%) had resistance to fluoroquinolones. The most common AESI were peripheral neuropathy (134, 28.4%) and electrolyte depletion (94, 19.9%). Acute kidney injury and myelosuppression were seen in 40 (8.5%) and 24 (5.1%) of patients, respectively. QT prolongation occurred in 7 (1.5%). Overall, 78.0% (358/458) had successful treatment outcomes, 8.9% died and 7.2% experienced treatment failure.
CONCLUSIONS
Concomitant use of Bdq and Dlm, along with linezolid and clofazimine, is safe and effective for MDR/RR-TB patients with extensive disease. Using these drugs concomitantly is a good therapeutic option for patients with resistance to many anti-TB drugs.
Concomitant use of bedaquiline (Bdq) and delamanid (Dlm) for multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) has raised concerns about a potentially poor risk-benefit ratio. Yet, this combination is an important alternative for patients infected with strains of TB with complex drug resistance profiles or who cannot tolerate other therapies. We assessed safety and treatment outcomes of MDR/RR-TB patients receiving concomitant Bdq and Dlm, along with other second-line anti-TB drugs.
METHODS
We conducted a multi-centric, prospective observational cohort study across 14 countries among patients receiving concomitant Bdq-Dlm treatment. Patients were recruited between April 2015 and September 2018 and were followed until the end of treatment. All serious adverse events and adverse events of special interest (AESI), leading to a treatment change, or judged significant by a clinician, were systematically monitored and documented.
RESULTS
Overall, 472 patients received Bdq and Dlm concomitantly. A large majority also received linezolid (89.6%) and clofazimine (84.5%). Nearly all (90.3%) had extensive disease; most (74.2%) had resistance to fluoroquinolones. The most common AESI were peripheral neuropathy (134, 28.4%) and electrolyte depletion (94, 19.9%). Acute kidney injury and myelosuppression were seen in 40 (8.5%) and 24 (5.1%) of patients, respectively. QT prolongation occurred in 7 (1.5%). Overall, 78.0% (358/458) had successful treatment outcomes, 8.9% died and 7.2% experienced treatment failure.
CONCLUSIONS
Concomitant use of Bdq and Dlm, along with linezolid and clofazimine, is safe and effective for MDR/RR-TB patients with extensive disease. Using these drugs concomitantly is a good therapeutic option for patients with resistance to many anti-TB drugs.
Journal Article > ResearchFull Text
Clin Infect Dis. 15 September 2022; Volume 75 (Issue 6); 1006-1013.; DOI:10.1093/cid/ciac019
Hewison CCH, Khan UT, Bastard M, Lachenal N, Coutisson S, et al.
Clin Infect Dis. 15 September 2022; Volume 75 (Issue 6); 1006-1013.; DOI:10.1093/cid/ciac019
RATIONALE
Safety of treatment for multidrug-resistant tuberculosis (MDR/RR-TB) can be an obstacle to treatment completion.
OBJECTIVES
Evaluate safety of longer MDR/RR-TB regimens containing bedaquiline and/or delamanid.
METHODS
Multicentre (16 countries), prospective, observational study, reporting incidence and frequency of clinically relevant adverse events of special interest (AESI) amongst patients who received MDR/RR-TB treatment containing bedaquiline and/or delamanid. The AESIs were defined a priori as important events caused by bedaquiline, delamanid, linezolid, injectables, and other commonly used drugs. Occurrence of these events was also reported by exposure to the likely causative agent.
RESULTS
Among 2296 patients, the most common clinically relevant AESIs were: peripheral neuropathy in 26.4%, electrolyte depletion in 26.0%, and hearing loss in 13.2% of patients. Per 1000 person-months of treatment, the incidence of these events was 21.5 (95% confidence interval [CI]: 19.8-23.2), 20.7 (95% CI: 19.1-22.4), and 9.7 (95% CI: 8.6-10.8), respectively. QT interval was prolonged in 2.7% or 1.8 (95% CI: 1.4-2.3)/1000 person-months of treatment. Patients who received injectables (N=925) and linezolid (N=1826) were most likely to experience events during exposure: Hearing loss, acute renal failure, or electrolyte depletion occurred in 36.8% or 72.8 (95%CI: 66.0-80.0) times/1000 person-months of injectable drug exposure. Peripheral neuropathy, optic neuritis and/or myelosuppression occurred in 27.8% or 22.8 (95% CI: 20.9-24.8) times/1000 patient-months of linezolid exposure.
CONCLUSIONS
Adverse events often related to linezolid and injectable drugs were more common than those frequently attributed to bedaquiline and delamanid. MDR-TB treatment monitoring schedules and individual drug durations should reflect expected safety profiles of drug combinations.
CLINICAL TRIALS REGISTRATION
NCT02754765
Safety of treatment for multidrug-resistant tuberculosis (MDR/RR-TB) can be an obstacle to treatment completion.
OBJECTIVES
Evaluate safety of longer MDR/RR-TB regimens containing bedaquiline and/or delamanid.
METHODS
Multicentre (16 countries), prospective, observational study, reporting incidence and frequency of clinically relevant adverse events of special interest (AESI) amongst patients who received MDR/RR-TB treatment containing bedaquiline and/or delamanid. The AESIs were defined a priori as important events caused by bedaquiline, delamanid, linezolid, injectables, and other commonly used drugs. Occurrence of these events was also reported by exposure to the likely causative agent.
RESULTS
Among 2296 patients, the most common clinically relevant AESIs were: peripheral neuropathy in 26.4%, electrolyte depletion in 26.0%, and hearing loss in 13.2% of patients. Per 1000 person-months of treatment, the incidence of these events was 21.5 (95% confidence interval [CI]: 19.8-23.2), 20.7 (95% CI: 19.1-22.4), and 9.7 (95% CI: 8.6-10.8), respectively. QT interval was prolonged in 2.7% or 1.8 (95% CI: 1.4-2.3)/1000 person-months of treatment. Patients who received injectables (N=925) and linezolid (N=1826) were most likely to experience events during exposure: Hearing loss, acute renal failure, or electrolyte depletion occurred in 36.8% or 72.8 (95%CI: 66.0-80.0) times/1000 person-months of injectable drug exposure. Peripheral neuropathy, optic neuritis and/or myelosuppression occurred in 27.8% or 22.8 (95% CI: 20.9-24.8) times/1000 patient-months of linezolid exposure.
CONCLUSIONS
Adverse events often related to linezolid and injectable drugs were more common than those frequently attributed to bedaquiline and delamanid. MDR-TB treatment monitoring schedules and individual drug durations should reflect expected safety profiles of drug combinations.
CLINICAL TRIALS REGISTRATION
NCT02754765
Conference Material > Video
Lachenal N, Hewison CCH, Berry C, Mitnick CD, Ahmed SM, et al.
MSF Scientific Days International 2022. 10 June 2022; DOI:10.57740/mq3w-0280
Conference Material > Abstract
Lachenal N, Hewison CCH, Berry C, Mitnick CD, Ahmed SM, et al.
MSF Scientific Days International 2022. 11 May 2022; DOI:10.57740/hs0k-1941
INTRODUCTION
Drug-resistant tuberculosis (DR-TB) carries significant morbidity and mortality risk. Care of DR-TB in pregnancy is even more challenging. A recent meta-analysis examining the impact of DR-TB on pregnancy outcomes found a higher than expected rate of maternal death, pregnancy loss, and a significant prevalence of low-birthweight infants. Anti-tubercular drugs such as bedaquiline and clofazimine have long half-lives and the impact of in-utero exposure is largely unknown. There is little information to help women, their family members, and clinicians make informed decisions about DR-TB treatment during pregnancy.
METHODS
Data on pregnancy outcomes were systematically collected as part of a pharmacovigilance programme supporting a clinical trial (TB-PRACTECAL; N=552) and a prospective cohort (endTB; N=2,906). We present the birth outcomes as reported to investigators by participants.
ETHICS
The endTB and TB-PRACTECAL studies were both approved by the local ethics committees in all recruiting countries and by the MSF Ethics Review Board. endTB was approved by the Partners Healthcare Human Research Committee, Boston, USA, and TB-PRACTECAL was approved by the London School of Hygiene and Tropical Medicine Ethics Committee, UK.
RESULTS
Between 01 April 2015 and 31 December 2021, 58 pregnancies in 53 women were notified from 10 different countries, predominantly Uzbekistan (14), Kazakhstan (13) and Pakistan (9). In 13 cases, pregnancy occurred after completion of tuberculosis treatment. Patients became pregnant a median of 260.5 (range, 0-727) days from treatment start; five women were 5-32 weeks pregnant at treatment start. There were no maternal deaths. 17.0% (9/53) of mothers changed or interrupted treatment during pregnancy. Treatment outcome was successful in 97.3% (36/37) of others in endTB and 100% (7/7) of mothers who completed follow-up in TB-PRACTECAL. Pregnancy outcome was known in 52 cases: 20 elective abortions, three miscarriages and 30 live births (one twin pregnancy). There were no stillbirths. Of the 30 live births, 29 occurred in mothers ever exposed to bedaquiline, 16 to clofazimine, 11 to a second-line injectable, 10 to pretomanid, and 7 to delamanid. Birth weight was known in 24/30 (80.0%) babies. Median weight was 3,015 (range, 1,270 to 4,200) grams. Two babies were born prematurely at 30 and 31 weeks. Low birthweight was reported in seven (29.2%; 7/24) babies. One low-birthweight baby died within four months of birth from complications unrelated to tuberculosis. One baby was treated for DR-TB. There were no reported birth malformations.
CONCLUSION
These results support evidence that effective DR-TB treatments may improve maternal outcomes and prevent perinatal transmission. How these perinatal outcomes compare to other cohorts not affected by TB in these settings or exposed to different TB treatments needs exploration. The factors contributing to low birthweight in babies born to mothers with DR-TB requires further research. A global registry is urgently needed to assist parents and clinicians with decision-making.
CONFLICTS OF INTEREST
The endTB project was funded by UNITAID (Geneva, Switzerland). Provision of delamanid within the endTB project was partially funded through a donation from Otsuka Company (Kyoto, Japan).
Drug-resistant tuberculosis (DR-TB) carries significant morbidity and mortality risk. Care of DR-TB in pregnancy is even more challenging. A recent meta-analysis examining the impact of DR-TB on pregnancy outcomes found a higher than expected rate of maternal death, pregnancy loss, and a significant prevalence of low-birthweight infants. Anti-tubercular drugs such as bedaquiline and clofazimine have long half-lives and the impact of in-utero exposure is largely unknown. There is little information to help women, their family members, and clinicians make informed decisions about DR-TB treatment during pregnancy.
METHODS
Data on pregnancy outcomes were systematically collected as part of a pharmacovigilance programme supporting a clinical trial (TB-PRACTECAL; N=552) and a prospective cohort (endTB; N=2,906). We present the birth outcomes as reported to investigators by participants.
ETHICS
The endTB and TB-PRACTECAL studies were both approved by the local ethics committees in all recruiting countries and by the MSF Ethics Review Board. endTB was approved by the Partners Healthcare Human Research Committee, Boston, USA, and TB-PRACTECAL was approved by the London School of Hygiene and Tropical Medicine Ethics Committee, UK.
RESULTS
Between 01 April 2015 and 31 December 2021, 58 pregnancies in 53 women were notified from 10 different countries, predominantly Uzbekistan (14), Kazakhstan (13) and Pakistan (9). In 13 cases, pregnancy occurred after completion of tuberculosis treatment. Patients became pregnant a median of 260.5 (range, 0-727) days from treatment start; five women were 5-32 weeks pregnant at treatment start. There were no maternal deaths. 17.0% (9/53) of mothers changed or interrupted treatment during pregnancy. Treatment outcome was successful in 97.3% (36/37) of others in endTB and 100% (7/7) of mothers who completed follow-up in TB-PRACTECAL. Pregnancy outcome was known in 52 cases: 20 elective abortions, three miscarriages and 30 live births (one twin pregnancy). There were no stillbirths. Of the 30 live births, 29 occurred in mothers ever exposed to bedaquiline, 16 to clofazimine, 11 to a second-line injectable, 10 to pretomanid, and 7 to delamanid. Birth weight was known in 24/30 (80.0%) babies. Median weight was 3,015 (range, 1,270 to 4,200) grams. Two babies were born prematurely at 30 and 31 weeks. Low birthweight was reported in seven (29.2%; 7/24) babies. One low-birthweight baby died within four months of birth from complications unrelated to tuberculosis. One baby was treated for DR-TB. There were no reported birth malformations.
CONCLUSION
These results support evidence that effective DR-TB treatments may improve maternal outcomes and prevent perinatal transmission. How these perinatal outcomes compare to other cohorts not affected by TB in these settings or exposed to different TB treatments needs exploration. The factors contributing to low birthweight in babies born to mothers with DR-TB requires further research. A global registry is urgently needed to assist parents and clinicians with decision-making.
CONFLICTS OF INTEREST
The endTB project was funded by UNITAID (Geneva, Switzerland). Provision of delamanid within the endTB project was partially funded through a donation from Otsuka Company (Kyoto, Japan).
Conference Material > Slide Presentation
Lachenal N, Hewison CCH, Berry C, Mitnick CD, Ahmed SM, et al.
MSF Scientific Days International 2022. 11 May 2022; DOI:10.57740/a29q-eq28